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From: B. Harris)
Subject: The Facts About the Concorde AZT Trial (was: AZT in Pregnant Women)
Date: Sat, 16 Aug 1997

In <01bcaa0f$8778bf00$> "Kathy Gorny"
<> writes:

>Steven B. Harris <> wrote in article
>> In <01bca98b$bcd8bbc0$> "Kathy Gorny"
>> <> writes:
>> >The thing about Concorde (and what is a hell of a lot more relevant in
>> >comparing it to this case) is that they found HIV positive people who
>> >took AZT tended to convert to full blown AIDS faster then those who
>> >did not. Which did dispute the original study.
>> This is false.  Feynman didn't say it was okay to comment on studies
>> you haven't read.
>>                                        Steve Harris, M.D.
>This is serious... I'm not joking here... but I am beginning to think
>there are two Concorde Studies? For I remember reading a review of the
>results of the study (back when it first came out) [...] Then I remember
>hearing they was a big dispute over these findings... there was talk the
>authors were going to change "something" I can't remember - and I
>remember thinking they succumbed to the drug company... and that's it.


   The Concorde trial, which is larger than all other AZT vs.
placebo trials combined, has been greatly misunderstood and
misused.  The design was simple: take 1749 people who were HIV
positive and fairly healthy clinically, and randomize them to
high dose AZT, or placebo.  Those who got sick or developed low
CD4 counts could be put on AZT later, if it turned out that they
had gotten AIDS or low counts while on placebo.

   Half of those who got AIDS turned out to be on placebo,
unfortunately.  The abstract below shows what happened after 3
years of study: AZT started early didn't affect total deaths,
total AIDS deaths, or total numbers of progression to AIDS.
These were the same in both groups, despite the fact that one
group got AZT from the beginning, while the other one got the
drug late or not at all (still consisting of more than half "AZT
virgins" who still hadn't gotten the active drug, after 3 years).

   Thus, the first important conclusion of Concorde: AZT use is
causing little or no AIDS in HIV-positive people, a conclusion
opposite to that which Duesberg and Lauritsen and many others had
been (and still are) asserting.  On the contrary, Concorde
demonstrates once and for all that clinically healthy HIV-
positive people develop AIDS just fine without AZT, and do so at
the same rate as people getting AZT.  In fact, in the Concorde
trial almost 20% of the HIV-positive AZT deferred group managed
to get AIDS or AIDS related complex (ARC) in three years on
placebo alone--- no AZT at all.  So much for the idea that
without AZT, the AIDS plague would not be with us.

   The deferred group, which had less than half as many people
who EVER got AZT at any time, should have had less than half as
much AIDS and AIDS death, *IF* AZT was a major cause of AIDS.
They didn't-- they had the same AIDS rate and AIDS death rate.
In fact, the people who got sick in the "immediate AZT" group had
been on AZT 5 times longer than those in the deferred group had
been on it, before they got sick.  Again, if AZT was the basic
cause of the sickness, these times would naturally have been
about the same.  A poison should take about the same time to
poison, no matter if given early or held until later, after all.
Note also that the AZT dose in Concorde is high-- about twice
what is standard today.

   The second important conclusion of the Concorde is that AZT
alone doesn't do any good if started too early in HIV disease.
This does not mean that AZT doesn't do any good for any HIV-
positive group of people-- merely that when it is given early in
HIV disease, before HIV-positive people would naturally be ill
with AIDS, the virus has 6-12 months to develop resistance to the
drug before there is much damage done to the immune system.  So
the AZT grace period is wasted if the drug is given before it is
needed, and AZT is thus best saved for later in the disease when
the immune system is failing.  Again, Concorde (and other
studies) suggest that AZT fails quickly against the virus when
used alone.  The Concorde did not contradict earlier studies in
which AZT had been used later in HIV disease, and there shown to
improve survival during the 6-12 months it was active (and the
immune system was failing).

   Concorde has now been run out to 5 years, though I don't think
these results have been published yet.  They show basically the
same-- still the same AIDS rate and AIDS death rate in both
groups.  However, later analyses of the Concorde now show that
total death rate is statistically higher in the group which was
started immediately on AZT, suggesting some long term toxicity of
this drug which overwhelms any benefit, but only after many years
of monotherapy (the trend does not become significant until after
more than 3 years into the trial).   Again, however, there is no
evidence in Concorde that this toxicity manifests itself as
AIDS-- rather the excess deaths in the early drug intervention
group appear due to auto accidents and suicides, if you look at
trends already apparent at 3 years.  Thus, while it seems likely
that high dose AZT used as monotherapy after many years may exact
a price in depression and incoordination, it does not do so in
opportunistic infections.  Finally, it needs to be remembered
that the death numbers in both groups were still within 90% of
each other, so the extra AZT is (again) NOT responsible for most
of the deaths in HIV-positive people the Concorde trial.
Statistically, it could not be, statistically.  AIDS, which had
nothing to do with AZT, still overwhelmed the death statistics in
Concorde, and was independent of AZT use.

   Over the years, it has been interesting to see what the AIDS
skeptics have had to say about Concorde.  This trial is a litmus
test for honest use of evidence.  There is no support in Concorde
for early use of AZT, but on the other hand, Concorde does pretty
well prove that AZT is not the cause of the AIDS plague.
Nevertheless, rather incredibly, you will see AIDS skeptics
arguing the opposite, and citing this study.   Thus, the AIDS/AZT
debate is not one between rational people making honestly
different interpretations of the same evidence.  Rather, it is a
debate too often between people using the evidence of trials like
Concorde, and other people simply ignoring, mis-citing, or
straight out *lying* about such evidence, which they are never
willing to discuss in detail.  Periodically it is necessary to
review the evidence to show which side is being dishonest in use
of this study, and which is not.

   Let the reader judge.  I have the paper and will be glad to
argue details with any skeptic so inclined.

                            -- Steven B. Harris, M.D.

TI  - Concorde: MRC/ANRS randomised double-blind controlled trial of
      immediate and deferred zidovudine in symptom-free HIV infection.
      Concorde Coordinating Committee [see comments]
AB  - Concorde is a double-blind randomised comparison of two policies
      of zidovudine treatment in symptom-free individuals infected with
      human immunodeficiency virus (HIV): (a) immediate zidovudine from
      the time of randomisation (Imm); and (b) deferred zidovudine
      (Def) until the onset of AIDS-related complex (ARC) or AIDS (CDC
      group IV disease) or the development of persistently low CD4 cell
      counts if the clinician judged that treatment was indicated.
      Between October, 1988, and October, 1991, 1749 HIV-infected
      individuals from centres in the UK, Ireland, and France were
      randomly allocated to zidovudine 250 mg four times daily (877
      Imm) or matching placebo (872 Def). Follow-up was to death or Dec
      31, 1992 (total 5419 person-years; median 3.3 years) and only 7%
      of the 1749 had not had a full clinical assessment after July 1,
      1992. Of those allocated to the Def group, 418 started zidovudine
      at some time during the trial, 174 (42%) of them at or after they
      were judged by the clinician to have developed ARC or AIDS
      (nearly all confirmed subsequently) and most of the remainder on
      the basis of low CD4 cell counts. Those in the Imm group spent
      81% of the time before ARC or AIDS on zidovudine compared with
      only 16% for those in the Def group. Despite the large difference
      in the amount of zidovudine between the two groups and the fact
      that the number of clinical endpoints (AIDS and death) in
      Concorde (347) outnumbers the total of those in all other
      published trials in symptom-free and early symptomatic infection,
      there was no statistically significant difference in clinical
      outcome between the two therapeutic policies. The 3-year
      estimated survival probabilities were 92% (95% CI 90-94%) in Imm
      and 94% (92-95%) in Def (log-rank p = 0.13), with no significant
      differences overall or in subgroup analyses by CD4 cell count at
      baseline. Similarly, there was no significant difference in
      progression of HIV disease: 3-year progression rates to AIDS or
      death were 18% in both groups, and to ARC, AIDS, or death were
      29% (Imm) and 32% (Def) (p = 0.18), although there was an
      indication of an early but transient clinical benefit in favour
      of Imm in progression to ARC, AIDS, or death. However, there was
      a clear difference in changes in CD4 cell count over time in the
      two groups.(ABSTRACT TRUNCATED AT 400 WORDS)
CM  - Comment in: Lancet 1994 Apr 9;343(8902):866-7 ; Comment in:
      Lancet 1994 May 28;343(8909):1355; discussion 1358 ; Comment in:
      Lancet 1994 May 28;343(8909):1355-6; discussion 1358 ; Comment
      in: Lancet 1994 May 28;343(8909):1356-7; discussion 1358 ;
      Comment in: Lancet 1994 May 28;343(8909):1357; discussion 1358 ;
      Comment in: Lancet 1994 May 28;343(8909):1357-8 ; Comment in: ACP
      J Club 1994 Nov-Dec;121(3):73
SO  - Lancet. 1994 Apr 9;343(8902):871-81.

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